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Protein

Toll-like receptor 4

Gene

Tlr4

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Cooperates with LY96 and CD14 to mediate the innate immune response to bacterial lipopolysaccharide (LPS) (PubMed:9851930, PubMed:9989976, PubMed:20133493). Acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:24380872). Also involved in LPS-independent inflammatory responses triggered by free fatty acids, such as palmitate. In complex with TLR6, promotes sterile inflammation in monocytes/macrophages in response to oxidized low-density lipoprotein (oxLDL) or amyloid-beta 42. In this context, the initial signal is provided by oxLDL- or amyloid-beta 42-binding to CD36. This event induces the formation of a heterodimer of TLR4 and TLR6, which is rapidly internalized and triggers inflammatory response, leading to the NF-kappa-B-dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway, as well as IL1B secretion. Binds electronegative LDL (LDL-) and mediates the cytokine release induced by LDL- (By similarity).By similarity8 Publications

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionReceptor
Biological processImmunity, Inflammatory response, Innate immunity

Enzyme and pathway databases

ReactomeiR-MMU-140534 via Death Receptors in the presence of ligand
R-MMU-166016 Toll Like Receptor 4 (TLR4) Cascade
R-MMU-166166 MyD88-independent TLR4 cascade
R-MMU-2562578 TRIF-mediated programmed cell death
R-MMU-5686938 Regulation of TLR by endogenous ligand
R-MMU-936964 Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon
R-MMU-937041 IKK complex recruitment mediated by RIP1
R-MMU-937072 TRAF6-mediated induction of TAK1 complex within TLR4 complex

Names & Taxonomyi

Protein namesi
Recommended name:
Toll-like receptor 4
Alternative name(s):
CD_antigen: CD284
Gene namesi
Name:Tlr4
Synonyms:Lps
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 4

Organism-specific databases

MGIiMGI:96824 Tlr4

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini26 – 638ExtracellularSequence analysisAdd BLAST613
Transmembranei639 – 659HelicalSequence analysisAdd BLAST21
Topological domaini660 – 835CytoplasmicSequence analysisAdd BLAST176

Keywords - Cellular componenti

Cell membrane, Endosome, Membrane

Pathology & Biotechi

Involvement in diseasei

The protein is encoded by the Lps locus, an important susceptibility locus, influencing the propensity to develop a disseminated Gram-negative infection.2 Publications

Disruption phenotypei

Animals with a double knockout of APOE and TLR4, fed a Western diet for 12 weeks, have less aortic plaque formation than single APOE knockout mice. They also show lower serum concentrations of IL1A, ILB and IL18.1 Publication

Keywords - Diseasei

Disease mutation

Chemistry databases

ChEMBLiCHEMBL1795167

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 25Sequence analysisAdd BLAST25
ChainiPRO_000003472326 – 835Toll-like receptor 4Add BLAST810

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi28 ↔ 391 Publication
Glycosylationi34N-linked (GlcNAc...) asparagine1 Publication1
Glycosylationi75N-linked (GlcNAc...) asparagine1 Publication1
Glycosylationi172N-linked (GlcNAc...) asparagine1 Publication1
Glycosylationi204N-linked (GlcNAc...) asparagine1 Publication1
Glycosylationi237N-linked (GlcNAc...) asparagine1 Publication1
Disulfide bondi280 ↔ 3041 Publication
Glycosylationi307N-linked (GlcNAc...) asparagine1 Publication1
Disulfide bondi388 ↔ 3891 Publication
Glycosylationi492N-linked (GlcNAc...) asparagine1 Publication1
Glycosylationi495N-linked (GlcNAc...) asparagine1
Glycosylationi524N-linked (GlcNAc...) asparagine1 Publication1
Glycosylationi572N-linked (GlcNAc...) asparagine1 Publication1
Glycosylationi575N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi580 ↔ 6061 Publication
Disulfide bondi582 ↔ 6251 Publication
Glycosylationi613N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi621N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi622N-linked (GlcNAc...) asparagineSequence analysis1

Keywords - PTMi

Disulfide bond, Glycoprotein

Proteomic databases

MaxQBiQ9QUK6
PaxDbiQ9QUK6
PRIDEiQ9QUK6

PTM databases

iPTMnetiQ9QUK6
PhosphoSitePlusiQ9QUK6

Expressioni

Tissue specificityi

Highly expressed in heart, spleen, lung and muscle. Lower levels are found in liver and kidney. Expressed in macrophages.1 Publication

Gene expression databases

BgeeiENSMUSG00000039005 Expressed in 161 organ(s), highest expression level in aortic valve
CleanExiMM_TLR4
ExpressionAtlasiQ9QUK6 baseline and differential
GenevisibleiQ9QUK6 MM

Interactioni

Subunit structurei

Belongs to the lipopolysaccharide (LPS) receptor, a multi-protein complex containing at least CD14, LY96 and TLR4 (PubMed:24380872). Binding to bacterial LPS leads to homodimerization (PubMed:20133493, PubMed:24380872, PubMed:22532668). Interacts with LY96 via the extracellular domain (PubMed:17803912, PubMed:22532668). Interacts with MYD88 (via the TIR domain). Interacts with TICAM2 and TIRAP (PubMed:24380872). Interacts with NOX4 (By similarity). Interacts with CNPY3 and HSP90B1; this interaction is required for proper folding in the endoplasmic reticulum (PubMed:18780723, PubMed:20865800). Interacts with MAP3K21; this interaction leads to negative regulation of TLR4 signaling (By similarity). Interacts with CD36, following CD36 stimulation by oxLDL or amyloid-beta 42, and forms a heterodimer with TLR6. The trimeric complex is internalized and triggers inflammatory response. LYN kinase activity facilitates TLR4-TLR6 heterodimerization and signal initiation (By similarity). Interacts with TICAM1 in response to LPS in a WDFY1-dependent manner (PubMed:25736436). Interacts with WDFY1 in response to LPS (PubMed:25736436). Interacts with SMPDL3B (PubMed:26095358). Interacts with CEACAM1; upon lipopolysaccharide stimulation, forms a complex including TLR4 and the phosphorylated form of SYK and CEACAM1, which in turn, recruits PTPN6 that dephosphorylates SYK, reducing the production of reactive oxygen species (ROS) and lysosome disruption, which in turn, reduces the activity of the inflammasome (PubMed:22496641). Interacts with RFTN1; the interaction occurs in response to lipopolysaccharide stimulation (By similarity).By similarity9 Publications

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi204224, 23 interactors
DIPiDIP-38573N
IntActiQ9QUK6, 14 interactors
STRINGi10090.ENSMUSP00000045770

Chemistry databases

BindingDBiQ9QUK6

Structurei

Secondary structure

1835
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliQ9QUK6
SMRiQ9QUK6
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ9QUK6

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Repeati54 – 75LRR 1Add BLAST22
Repeati78 – 99LRR 2Add BLAST22
Repeati102 – 123LRR 3Add BLAST22
Repeati126 – 147LRR 4Add BLAST22
Repeati150 – 171LRR 5Add BLAST22
Repeati175 – 198LRR 6Add BLAST24
Repeati204 – 224LRR 7Add BLAST21
Repeati226 – 247LRR 8Add BLAST22
Repeati248 – 269LRR 9Add BLAST22
Repeati329 – 349LRR 10Add BLAST21
Repeati350 – 370LRR 11Add BLAST21
Repeati372 – 392LRR 12Add BLAST21
Repeati398 – 420LRR 13Add BLAST23
Repeati421 – 442LRR 14Add BLAST22
Repeati446 – 467LRR 15Add BLAST22
Repeati470 – 490LRR 16Add BLAST21
Repeati495 – 516LRR 17Add BLAST22
Repeati519 – 540LRR 18Add BLAST22
Repeati543 – 564LRR 19Add BLAST22
Domaini576 – 627LRRCTAdd BLAST52
Domaini670 – 816TIRPROSITE-ProRule annotationAdd BLAST147

Domaini

The TIR domain mediates interaction with NOX4.By similarity

Sequence similaritiesi

Belongs to the Toll-like receptor family.Curated

Keywords - Domaini

Leucine-rich repeat, Repeat, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG4641 Eukaryota
COG4886 LUCA
GeneTreeiENSGT00760000119006
HOGENOMiHOG000037951
HOVERGENiHBG018823
InParanoidiQ9QUK6
KOiK10160
OMAiFHLMLLA
OrthoDBiEOG091G01RC
PhylomeDBiQ9QUK6
TreeFamiTF351113

Family and domain databases

Gene3Di3.40.50.10140, 1 hit
3.80.10.10, 1 hit
InterProiView protein in InterPro
IPR000483 Cys-rich_flank_reg_C
IPR001611 Leu-rich_rpt
IPR003591 Leu-rich_rpt_typical-subtyp
IPR032675 LRR_dom_sf
IPR000157 TIR_dom
IPR027168 TLR4
IPR035897 Toll_tir_struct_dom_sf
PANTHERiPTHR44568 PTHR44568, 1 hit
PfamiView protein in Pfam
PF13855 LRR_8, 2 hits
PF01582 TIR, 1 hit
SMARTiView protein in SMART
SM00369 LRR_TYP, 8 hits
SM00082 LRRCT, 1 hit
SM00255 TIR, 1 hit
SUPFAMiSSF52200 SSF52200, 1 hit
PROSITEiView protein in PROSITE
PS50104 TIR, 1 hit

Sequence (1+)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry has 1 described isoform and 1 potential isoform that is computationally mapped.Show allAlign All

Q9QUK6-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MMPPWLLART LIMALFFSCL TPGSLNPCIE VVPNITYQCM DQKLSKVPDD
60 70 80 90 100
IPSSTKNIDL SFNPLKILKS YSFSNFSELQ WLDLSRCEIE TIEDKAWHGL
110 120 130 140 150
HHLSNLILTG NPIQSFSPGS FSGLTSLENL VAVETKLASL ESFPIGQLIT
160 170 180 190 200
LKKLNVAHNF IHSCKLPAYF SNLTNLVHVD LSYNYIQTIT VNDLQFLREN
210 220 230 240 250
PQVNLSLDMS LNPIDFIQDQ AFQGIKLHEL TLRGNFNSSN IMKTCLQNLA
260 270 280 290 300
GLHVHRLILG EFKDERNLEI FEPSIMEGLC DVTIDEFRLT YTNDFSDDIV
310 320 330 340 350
KFHCLANVSA MSLAGVSIKY LEDVPKHFKW QSLSIIRCQL KQFPTLDLPF
360 370 380 390 400
LKSLTLTMNK GSISFKKVAL PSLSYLDLSR NALSFSGCCS YSDLGTNSLR
410 420 430 440 450
HLDLSFNGAI IMSANFMGLE ELQHLDFQHS TLKRVTEFSA FLSLEKLLYL
460 470 480 490 500
DISYTNTKID FDGIFLGLTS LNTLKMAGNS FKDNTLSNVF ANTTNLTFLD
510 520 530 540 550
LSKCQLEQIS WGVFDTLHRL QLLNMSHNNL LFLDSSHYNQ LYSLSTLDCS
560 570 580 590 600
FNRIETSKGI LQHFPKSLAF FNLTNNSVAC ICEHQKFLQW VKEQKQFLVN
610 620 630 640 650
VEQMTCATPV EMNTSLVLDF NNSTCYMYKT IISVSVVSVI VVSTVAFLIY
660 670 680 690 700
HFYFHLILIA GCKKYSRGES IYDAFVIYSS QNEDWVRNEL VKNLEEGVPR
710 720 730 740 750
FHLCLHYRDF IPGVAIAANI IQEGFHKSRK VIVVVSRHFI QSRWCIFEYE
760 770 780 790 800
IAQTWQFLSS RSGIIFIVLE KVEKSLLRQQ VELYRLLSRN TYLEWEDNPL
810 820 830
GRHIFWRRLK NALLDGKASN PEQTAEEEQE TATWT
Length:835
Mass (Da):95,519
Last modified:May 1, 2000 - v1
Checksum:i9C83B59F9A220C17
GO

Computationally mapped potential isoform sequencesi

There is 1 potential isoform mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
A2BHU8A2BHU8_MOUSE
Toll-like receptor 4
Tlr4 RP24-209H15.1-004
154Annotation score:

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti87 – 154CEIET…TLKKL → EMNTESKSSEAHALALSHIL SPCQPSRRKLRVKLGSLSYQ RAEEGVRSSEIGYSCLHVDT RHDINAVD (PubMed:16141072).CuratedAdd BLAST68

Polymorphismi

Interstrain analyzes reveals that TLR4 is a polymorphic protein and that the extracellular domain is far more variable than the cytoplasmic domain, which is variable at the C-terminal.1 Publication

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural varianti94D → N in strain: KK/HLJ. 1 Publication1
Natural varianti209M → I in strain: A/J, BALB/cJ, P/J, SODL/EI, SEA/GNJ, NZW/LACJ and VM/DK. 1 Publication1
Natural varianti219D → G in strain: SEA/GNJ. 1 Publication1
Natural varianti254V → I in strain: A/J, BALB/cJ and SEA/GNJ. 1 Publication1
Natural varianti423Q → L in strain: SEA/GNJ. 1 Publication1
Natural varianti477A → S in strain: P/J. 1 Publication1
Natural varianti516T → A in strain: LP/J. 1 Publication1
Natural varianti593E → D in strain: A/J, BALB/cJ, P/J, SODL/EI, SEA/GNJ, NZW/LACJ and VM/DK. 1 Publication1
Natural varianti600N → I in strain: KK/HLJ. 1 Publication1
Natural varianti607A → V in strain: P/J. 1 Publication1
Natural varianti637V → I in strain: P/J. 1 Publication1
Natural varianti712P → H in Lps-tolerant mice. 2 Publications1
Natural varianti761R → H in strain: A/J, BALB/cJ, SODL/EI, SEA/GNJ, NZW/LACJ and VM/DK. 1 Publication1
Natural varianti811N → K in strain: P/J. 1 Publication1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF095353 mRNA Translation: AAC99411.1
AF110133 mRNA Translation: AAD29272.1
AF185285 mRNA Translation: AAF04278.1
AF177767 Genomic DNA Translation: AAF05317.1
AK014533 mRNA No translation available.
CCDSiCCDS18271.1
RefSeqiNP_067272.1, NM_021297.3
UniGeneiMm.38049

Genome annotation databases

EnsembliENSMUST00000048096; ENSMUSP00000045770; ENSMUSG00000039005
GeneIDi21898
KEGGimmu:21898
UCSCiuc008thv.1 mouse

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF095353 mRNA Translation: AAC99411.1
AF110133 mRNA Translation: AAD29272.1
AF185285 mRNA Translation: AAF04278.1
AF177767 Genomic DNA Translation: AAF05317.1
AK014533 mRNA No translation available.
CCDSiCCDS18271.1
RefSeqiNP_067272.1, NM_021297.3
UniGeneiMm.38049

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2Z64X-ray2.84A27-625[»]
3VQ1X-ray2.70A/B22-627[»]
3VQ2X-ray2.48A/B22-627[»]
5IJBX-ray2.91A/B26-544[»]
5IJCX-ray2.57A/B26-544[»]
5IJDX-ray2.70A/B26-544[»]
ProteinModelPortaliQ9QUK6
SMRiQ9QUK6
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi204224, 23 interactors
DIPiDIP-38573N
IntActiQ9QUK6, 14 interactors
STRINGi10090.ENSMUSP00000045770

Chemistry databases

BindingDBiQ9QUK6
ChEMBLiCHEMBL1795167

PTM databases

iPTMnetiQ9QUK6
PhosphoSitePlusiQ9QUK6

Proteomic databases

MaxQBiQ9QUK6
PaxDbiQ9QUK6
PRIDEiQ9QUK6

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000048096; ENSMUSP00000045770; ENSMUSG00000039005
GeneIDi21898
KEGGimmu:21898
UCSCiuc008thv.1 mouse

Organism-specific databases

CTDi7099
MGIiMGI:96824 Tlr4

Phylogenomic databases

eggNOGiKOG4641 Eukaryota
COG4886 LUCA
GeneTreeiENSGT00760000119006
HOGENOMiHOG000037951
HOVERGENiHBG018823
InParanoidiQ9QUK6
KOiK10160
OMAiFHLMLLA
OrthoDBiEOG091G01RC
PhylomeDBiQ9QUK6
TreeFamiTF351113

Enzyme and pathway databases

ReactomeiR-MMU-140534 via Death Receptors in the presence of ligand
R-MMU-166016 Toll Like Receptor 4 (TLR4) Cascade
R-MMU-166166 MyD88-independent TLR4 cascade
R-MMU-2562578 TRIF-mediated programmed cell death
R-MMU-5686938 Regulation of TLR by endogenous ligand
R-MMU-936964 Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon
R-MMU-937041 IKK complex recruitment mediated by RIP1
R-MMU-937072 TRAF6-mediated induction of TAK1 complex within TLR4 complex

Miscellaneous databases

EvolutionaryTraceiQ9QUK6
PROiPR:Q9QUK6
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000039005 Expressed in 161 organ(s), highest expression level in aortic valve
CleanExiMM_TLR4
ExpressionAtlasiQ9QUK6 baseline and differential
GenevisibleiQ9QUK6 MM

Family and domain databases

Gene3Di3.40.50.10140, 1 hit
3.80.10.10, 1 hit
InterProiView protein in InterPro
IPR000483 Cys-rich_flank_reg_C
IPR001611 Leu-rich_rpt
IPR003591 Leu-rich_rpt_typical-subtyp
IPR032675 LRR_dom_sf
IPR000157 TIR_dom
IPR027168 TLR4
IPR035897 Toll_tir_struct_dom_sf
PANTHERiPTHR44568 PTHR44568, 1 hit
PfamiView protein in Pfam
PF13855 LRR_8, 2 hits
PF01582 TIR, 1 hit
SMARTiView protein in SMART
SM00369 LRR_TYP, 8 hits
SM00082 LRRCT, 1 hit
SM00255 TIR, 1 hit
SUPFAMiSSF52200 SSF52200, 1 hit
PROSITEiView protein in PROSITE
PS50104 TIR, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiTLR4_MOUSE
AccessioniPrimary (citable) accession number: Q9QUK6
Secondary accession number(s): Q9D691, Q9QZF5, Q9Z203
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 11, 2002
Last sequence update: May 1, 2000
Last modified: November 7, 2018
This is version 170 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  3. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
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